Hepatocellular arcinoma (HCC) is responsible for more than 500,000 estimated deaths worldwide each year. The lack of effective therapies for this disease necessitates novel therapeutic approaches. Oncolytic viral vectors, such as those based on vesicular stomatitis virus (VSV), are a promising new anticancer platform for HCC. While the oncolytic effects of VSV are clearly defined, the mechanisms underlying this antitumor activity are incompletely understood. In addition to direct cytolysis, viral infection of cancer cels elicits specific and nonspecific immune responses, thus overcoming immunological tolerance to the tumor. The type III interferon (IFN) family of antiviral cytokines (IL-29, 28A, 28B; also known as IFN-?1, 2, and 3) have antiviral and immunomodulatory properties, and inhibit tumor progression in mouse models of cancer. We hypothesize that expression of these cytokines from VSV will improve oncolytic activity through both stimulatory effects on the immune response and by increasing selectivity of the virus for tumor cells. Our preliminary data show that VSV expressing IL-28A is attenuated in cultured IL-28-responsive immortalized hepatocytes and after intranasal delivery to mice in vivo. Using a mouse model of HCC, we will examine the hypothesis that expression of IL-28A from a VSV vector will augment oncolytic activity. We will then investigate the mechanisms by which IL-28 expressed from VSV enhances the oncolytic activity by performing studies to determine the contribution of immunostimulatory effects on NK cells and T cells, increased selectivity of the virus for IL-28-nonresponsive tumor cells, and anti proliferative/pro-apoptotic actions. The studies proposed here will help elucidate the antitumor mechanisms responsible for the oncolytic activity of VSV and IL-28. Illumination of these mechanisms is crucial for better understanding the complex and dynamic relationship between the host immune system, the tumor, and the virus. By uniting the individually proven anticancer activities of VSV and IL-28, these studies will thereby inform the creation of more potent engineered oncolytic viral vectors.